isoflurane, USP) Liquid For Inhalation
DRUG DESCRIPTION
FORANE (isoflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 1-chloro-2, 2,2-trifluoroethyl difluoromethyl ether, and its structural formula is:
Some physical constants are:
Molecular weight..............................184.5
Boiling point at 760 mm Hg...................48.5°C (uncorr.)
Refractive index n20D..........................1.2990-1.3005
Specific gravity 25°/25°C....................1.496
Vapor pressure in mm Hg**
20°C........238
25°C...........295
30°C...........367
35°C...........450
**Equation for vapor pressure calculation:
log10Pvap = A + B/T where A = 8.056 T
B = -1664.58
T = °C + 273.16 (Kelvin)
Partition coefficients at 37°C:
Water/gas.................0.61
Blood/gas.................1.43
Oil/gas.......................90.8
Partition coefficients at 25°C - rubber and plastic
Conductive rubber/gas.................62.0
Butyl rubber/gas.................75.0
Polyvinyl chloride/gas.................110.0
Polyethylene/gas.................~2.0
Polyurethane/gas................. ~1.4
Polyolefin/gas .................~1.1
Butyl acetate/gas................. ~2.5
Purity by gas chromatography ................. > 99.9%
Lower limit of flammability in oxygen or nitrous oxide at 9 joules/sec. and 23°C.................None
Lower limit of flammability in oxygen or nitrous oxide at 900 joules/sec. and 23°C.................Greater than useful concentration in anesthesia.
Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in indirect sunlight in clear, colorless glass for five years, as well as samples directly exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged in composition as determined by gas chromatography. Isoflurane in one normal sodium methoxide-methanol solution, a strong base, for over six months consumed essentially no alkali, indicative of strong base stability. Isoflurane does not decompose in the presence of soda lime (at normal operating temperatures), and does not attack aluminum , tin, brass, iron or copper.
INDICATIONS
FORANE (isoflurane, USP) may be used for induction and maintenance of general anesthesia . Adequate data have not been developed to establish its application in obstetrical anesthesia.
DOSAGE AND ADMINISTRATION
Premedication
Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by FORANE (isoflurane, USP), and the heart rate tends to be increased. The use of anticholinergic drugs is a matter of choice.
Inspired Concentration
The concentration of isoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using:
a. Vaporizers calibrated specifically for isoflurane;
b. Vaporizers from which delivered flows can be calculated, such as vaporizers delivering a saturated vapor, which is then diluted. The delivered concentration from such a vaporizer may be calculated using the formula:
% isoflurane = 100 PvFv/FT (PA - PV)
Where: :
PA = Pressure of atmosphere
PV = Vapor pressure of isoflurane
FV=Flow of gas through vaporizer (mL/min)
FT = Total gas flow (mL/min)
Isoflurane contains no stabilizer. Nothing in the agent alters calibration or operation of these vaporizers.
Induction
Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath holding, or laryngospasm. These difficulties may be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate. Inspired concentrations of 1.5 to 3.0% isoflurane usually produce surgical anesthesia in 7 to 10 minutes.
Maintenance
Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration when nitrous oxide is used concomitantly. An additional 0.5 to 1.0% may be required when isoflurane is given using oxygen alone. If added relaxation is required, supplemental doses of muscle relaxants may be used.
The level of blood pressure during maintenance is an inverse function of isoflurane concentration in the absence of other complicating problems. Excessive decreases may be due to depth of anesthesia and in such instances may be corrected by lightening anesthesia.
SIDE EFFECTS
Adverse reactions encountered in the administration of FORANE (isoflurane, USP) are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression , hypotension and arrhythmias.
Shivering, nausea , vomiting and ileus have been observed in the postoperative period.
As with all other general anesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress . See WARNINGS for information regarding malignant hyperthermia and elevated carboxyhemoglobin levels.
During marketing, there have been rare reports of mild, moderate and severe (some fatal) postoperative hepatic dysfunction and hepatitis .
FORANE (isoflurane USP) has also been associated with perioperative hyperkalemia (see WARNINGS ).
There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including FORANE (isoflurane USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of FORANE (isoflurane USP) to these events cannot be established with certainty.
DRUG INTERACTIONS
Isoflurane potentiates the muscle relaxant effect of all muscle relaxants, most notably nondepolarizing muscle relaxants, and MAC (minimum alveolar concentration) is reduced by concomitant administration of N2O. See CLINICAL PHARMACOLOGY .
WARNINGS
Perioperative Hyperkalemia
Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy , appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia , none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
Malignant Hyperthermia
In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia , tachypnea , cyanosis , arrhythmias, and unstable blood pressure . (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia , etc.) An increase in overall metabolism may be reflected in an elevated temperature, (which may rise rapidly early or late in the case, but usually is not absorption the first sign of augmented metabolism) and an increased usage of the CO2 and pH may decrease, and hyperkalemia and a base deficit system (hot canister). PaO2 may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium , and application of supportive therapy . Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management). Renal failure may appear later, and urine flow should be sustained if possible.
Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory depression increase as anesthesia is deepened.
Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions.
FORANE (isoflurane, USP) markedly increases cerebral blood flow at deeper levels of anesthesia. There may be a transient rise in cerebral spinal fluid pressure, which is fully reversible with hyperventilation .
PRECAUTIONS
General
As with any potent general anesthetic, FORANE (isoflurane, USP) should only be administered in an adequately equipped anesthetizing environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anesthetized patient.
Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease 4,5,6,7.
FORANE (isoflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide, which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber canister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of FORANE (isoflurane, USP).
As with other halogenated anesthetic agents, FORANE (isoflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS ).
Laboratory Tests
Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Swiss ICR mice were given isoflurane to determine whether such exposure might induce neoplasia . Isoflurane was given at ½, and 1/32 MAC for four in-utero exposures and for 24 exposures to the pups during the first nine weeks of life. The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice, which were given the same background gases, but not the anesthetic.
Pregnancy
Pregnancy Category C
Isoflurane has been shown to have a possible anesthetic-related fetotoxic effect in mice when given in doses 6 times the human dose. There are no adequate and well-controlled studies in pregnant women. Isoflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus .
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isoflurane is administered to a nursing woman.
OVERDOSE
In the event of overdosage, or what may appear to be overdosage, the following action should be taken:
Stop drug administration, establish a clear airway , and initiate assisted or controlled ventilation with pure oxygen .
CONTRAINDICATIONS
Known sensitivity to FORANE (isoflurane, USP) or to other halogenated agents. Known or suspected genetic susceptibility to malignant hyperthermia .
CLINICAL PHARMACOLOGY
FORANE (isoflurane, USP) is an inhalation anesthetic . The MAC (minimum alveolar concentration) in man is as follows:
Age 100% Oxygen 70% N20
26±4 1.28 0.56
44±7 1.15 0.50
64±5 1.05 0.37
Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency, which limits the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded . The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. RESPIRATION MUST BE MONITORED CLOSELY AND SUPPORTED WHEN NECESSARY. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane.
Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate , which compensates for a reduction in stroke volume . The hypercapnia , which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. Isoflurane does not sensitize the myocardium to exogenously administered epinephrine in the dog. Limited data indicate that subcutaneous injection of 0.25 mg of epinephrine (50 mL of 1:200,000 solution) does not produce an increase in ventricular arrhythmias in patients anesthetized with isoflurane.
Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of muscle relaxants. ALL COMMONLY USED MUSCLE RELAXANTS ARE MARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND WITH THE NONDEPOLARIZING TYPE. Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane. All commonly used muscle relaxants are compatible with isoflurane.
Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models 1,2; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model ("coronary steal")3. Clinical studies to date evaluating myocardial ischemia , infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease4,5,6,7.
Pharmacokinetics
Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites.
summary
A clear, colourless, volatile liquid with a slight pungent
odour. B.p. about 49°. It is non-flammable.
Practically insoluble in water, miscible with common organic
solvents and with fats and oils. Store in airtight containers.
Adverse Effects
As with other halogenated anaesthetics, respiratory
depression, hypotension, arrhythmias, and malig-
nant hyperthermia have been reported. Isoflurane
differs from halothane and enflurane in that it pro-
duces less cardiac depression than either drug and
heart rate may be increased. Also isoflurane sensitis-
es the myocardium to sympathomimetics to a lesser
extent than halothane and enflurane. The incidence
of cardiac arrhythmias is lower with isoflurane than
with halothane. Shivering, nausea, and vomiting
have been reported in the postoperative period.
Induction with isoflurane is not as smooth as with
halothane and this may be connected with its pun-
gency; breath holding, coughing, and laryngospasm
may occur.
See also Adverse Effects of General Anaesthetics,halothane.
Cattennole er aJ. in comparing isoflurane and halothane for
outpatient dental anaesthesia in children considered that iso-
flurane would produce fewer arrhythmias than halothane. but
that the ease of induction and the quality of anaesthesia was
inferior to that with halothane. McAteer- also found a higher
incidence of coughing, salivation, and laryngospasm with iso-
flurane than halothane but felt that it could be used as an al-
ternative.
Further information on the adverse effects profile of isoflu-
rane can be obtained from the report of and commentaries on
an extensive multicentre study of patients undergoing anaes-
thesia with this agent.-'j
Effeetf on the blood. The development of carboxyhaemo-
globinaemia in patients anaesthetised with volatile anaesthet-
ics is discussed under Precautions, below.
Effects on the cardiovascular system. Isoflurane is con-
sidered to produce less cardiovascular depression than haloth-
ane. However, results of a study by one group of workers
suggest that while this may be true for young patients, in eld-
erly patients isoflurane appears to have a cardiac depressant
effect similar to that of halothane.
CORONARY CIRCULATION. Halothane, enflurene. and isoflurane
decrease coronary perfusion pressure, coronary blood flow,
veniricular function, and myocardial oxygen demand. Ha-
lothane and enflurane have a variable effect on coronary vas-
cular resistance, but isoflurane dilates coronary vessels.
There has been concern over the potential of isoflurane to pro-
duce coronary steal and whether this effect is detrimental in
patients with ischaemic heart diseased However, despite ,con-
flicting results of individual studies a review concluded
that isoflurane could be used safely even in high-risk patients
with coronary artery disease provided that blood pressure and
heart rate were maintained close to base-line levels.
Effects on the kidneys. See under Metabolism in Pharma-
cokinctics, below.
Effects on the liver. Of 45 cases of isoflurane-associated
hepatotoxicity reported to the PDA between 1981 and 1984
there was some other cause for the liver damage in 29. While
isoflurane might have been one of the causes of the damage in
the other 16 cases, there was not a reasonable likelihood of an
association between isoflurane and postoperative liver im-
pairment. A subsequent case report of hepatic necrosis and
death following surgery was possibly attributable to isoflu-
rane.-
See also under the Adverse Effects of Halothane.
Effects on the nervous system. Seizures associated with
induction of anaesthesia with isoflurane have been reported in
patients without known neurological abnormalities and not
undergoing neurosuteery. However, data from a retrospec-
tive analysis of patients undergoing intracranial surgery indi-
cated that when convulsions occurred postoperatively in these
conditions, it was the neurosurgical procedures rather than the
anaesthetics that were responsible.)
Effects on the respiratory tract. A study conducted
mainly in adults found that humidification of anaesthetic mix
tures containing isoflurane could reduce respiratory compli-
cations such as coughing, laryngospasm, and breath-holding
that were usually associated with the use of isoflurane for in
duction. However, a similar study' in children failed to con-
firm these findings.
Precautions
As with other halogenated anaesthetics, patients
with known or suspected susceptibility to malignant
hyperthermia should not be anaesthetised with iso-
flurane. It has been reported to increase the cerebro-
spinal pressure and should be used with caution in
patients with raised intracranial pressure. Isoflurane
relaxes the uterine muscle. In order to minimise the
risk of developing elevated carboxyhaemoglobin
levels, carbon dioxide absorbents in anaesthetic ap-
paratus should not be allowed to dry out when deliv-
ering volatile anaesthetics such as isoflurane.
See also Precautions for General Anaesthetics,
Like halothane.
Significant carboxyhaemoglobinaemia may develop during
anaesthesia with volatile anaesthetics given by circle breath-
ing systems containing carbon dioxide absorbents. The ef-
fect is only seen when the absorbent (usually barium
hydroxide lime) has became excessively dried out.
Interactions
The effects of competitive neuromuscular blockers
such as atracurium are enhanced by isoflurane . Care is
advised if adrenaline and other
sympathomimetics are given during isoflurane anaesthesia.
See also Interactions of General Anaesthetics,halothane.
General anaesthetics. For a report that isoflurane increas-
es serum concentrations of propofol, see propofol.
Pharmacokinetics
Isoflurane is absorbed on inhalation. The blood/gas
coefficient is lower than that of enflurane or haloth-
ane. It is mostly excreted unchanged through the
lungs. About 0.2% of administered isoflurane is me-
tabolised mainly to inorganic fluoride.
Reviews.
Metabolism. In 26 patients sedated with isoflurane for
24 hours, plasma fluoride ion concentration increased from a
mean of 4.03 nmol per mL to 13.57 nmol per mL in 12 hours
after stopping sedation.' These fluoride concentrations were
considered to be too low to cause clinical renal dysfunction.
In 30 patients sedated with isoflurane for up to 127 hours
(mean duration was 36 hours), mean plasma fluoride ion con-
centration increased to 20.01 nmol per mL during sedation
and continued rising for 16 hours after discontinuing isoflu-
rane to a maximum mean concentration of 2534 nmol per
mt: thereafter, levels gradually declined to normal values by
the fifth day. Despite the increased plasma fluoride ion con-
centrations. no biochemical or clinical evidence of deteriora-
tion in renal function was found. Administration ofisoflurane
for 34 days to a patient with tetanus who required sedation to
facilitate mechanical ventilation resulted in sustained
fluoride
ion concentrations of 50 nmol per mL and a peak concentra-
tion of 87 nmol per mt. Although such concentrations are
considered to be potentially nephrotoxic no clinical effect on
renal function was found.
Uses and Administration
Isoflurane is a volatile halogenated anaesthetic ad-
ministered by inhalation. It is an isomer of enflurane
and has anaesthetic actions similar to those of ha-
lothane . Isoflurane has a minimum alveolar
concentration (MAC) value ranging
from 1.05% in the elderly to 1.87% in infants. It is
employed in the induction and maintenance of an-
aesthesia although induction is more often
carried out using an intravenous anaesthetic with
isoflurane being given for maintenance. Isoflurane is
also used in subanaesthetic doses to provide analge-
sia in obstetrics and other painful procedures.
Isoflurane is administered using a calibrated vapor-
iser. If it is used for induction then it is given with
oxygen or oxygen and nitrous oxide and induction
should start with an isoflurane concentration of
0.5% v/v increased to 1.5 to 3.0% v/v which gener-
ally produces surgical anaesthesia within 10 min-
utes. Its pungency may limit the rate of induction.
Anaesthesia may be maintained with a concentra-
tion of 1.0 to 2.5% v/v with oxygen and nitrous ox-
ide; 1.5 to 3.5% v/v may be required if used only
with oxygen. Isoflurane 0.5 to 0.75% v/v with oxy-
gen and nitrous oxide is suitable to maintain anaes-
thesia for caesarean section. Although isoflurane is
reported to possess muscle relaxant properties, neu-
romuscular blockers may nevertheless be required.
Recovery is rapid.
Reviews.
Anaesthesia. CAESAREAN SECTION. Isoflurane 0.8% v/v has
been found to be a suitable supplement to nitrous oxide-oxy-
gen anaesthesia for patients undergoing caesarean section.' It
has been suggested- that an overpressure technique might be
of use to further reduce awareness in such patients. Adminis-
tration of isoflurane at a concentration of 2% v/v for 5 min-
utes followed by concentrations of 1.5% v/v for the next 5
minutes and 0.8% v/v thereafter produced higher arterial con-
centrations of isoflurane in patients undergoing caesarean
section than when it was given at a concentration of 1% v/v
throughout.?
Pain. Isoflurane is used in subanaesthetic doses to provide
analgesia in obstetrics and other painful procedures but studies
have been unable to confirm that it had an analgesic effect at
subanaesthetic concentrations. The use of isoflurane 0.2 or 0.25%
v/v in a mixture of nitrous oxide 50% v/v and oxygen 50% v/v has
been studied.
Sedation. INTENSIVE CARE. The various drugs used to provide
sedation in intensive care are discussed on p.638. Isoflurane
is not usually considered for such a purpose but in a compar-
ative 24-hour study' in 60 patients requiring mechanical ven-
tilation. isoflurane O.I to 0.6% v/v in an air-oxygen mixture
produced satisfactory sedation for a greater proportion of
time than did the continuous infusion of midazolam 0.01 to
0.20 mg per kg body-weight per hour. Patients given isoflu-
rane also recovered more rapidly. Isoflurane has also been
used successfully for sedation in a 3-year-old infant admitted
to intensive care with pneumonia, a complication of the
child's myasthenia gravis.- However, there has been some
concern over high plasma fluoride concentrations following
prolonged use of isoflurane (see under Metabolism in Phar-
macokinetics. above).
Status epilepticus Anaesthesia in conjunction with assist-
ed ventilation may be instituted to control refractory tonic-
clonic status epilepticus. A short-acting barbiturate
such as thiopentone is usually used. Despite there being rare
reports of seizures associated with the use of isoflurane in an-
aesthetic procedures (see under Adverse Effects, above) con-
centrations of 0.5 to 1% v/v have been used successfully in
isolated patients to control refractory convulsive status epi-
lepticus. Although some consider that isoflurane-induced
coma may be more easy to control than barbiturate-induced
coma. the use of isoflurane may be limited by the need for
special anaesthetic equipment and continuous EEG monitoring.